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Phenanthrenes from Juncus effusus with anxiolytic and sedative activities

Taylor & Francis
Natural Product Research
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Abstract

Eight phenanthrenes, 7-carboxy-2-hydroxy-1-methyl-5-vinyl-phenanthrene (1); 2,7-dihydroxy-1-methyl-5-aldehyde-9,10-dihydrophenanthrene (2); dehydroeffusol (3); dehydrojuncusol (4); 7-carboxy-2-hydroxy-1-methyl-5-vinyl-9,10-dihydrophenanthrene (5); 8-carboxy-2-hydroxy-1-methyl-5-vinyl-9,10-dihydrophenanthrene (6); effusol (7) and juncusol (8), were isolated from the aerial part of Juncus effusus. Compounds 1 and 2 were identified as new constituents. Compounds 7 and 8 showed anxiolytic and sedative activities.

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... The 1 H NMR spectrum (Table 2) showed the two sharp singlets of the H-11 and H-11′ methyls, the two benzylic multiplets H-9′ and H-10′ methylenes, six double doublets of H-12, H-13 and H-12′, H-13′ the two vinyl groups and the aromatic singlets of the H-4′ and H-6 protons and the doublets of the H-3, H-4, H-9, H-10, H-6′ and H-8′ protons. These data matched those of a phenanthrene, dehydroeffusol [24,25] and a 9,10-dihydrophenanthrene, effusol [22][23][24] unities. The linkage between the unities was attributed on the basis of 1 H-1 H COSY and HMBC experiments (Fig. 2). ...
... The 1 H NMR spectrum (Table 2) showed the two sharp singlets of the H-11 and H-11′ methyls, the two benzylic multiplets H-9′ and H-10′ methylenes, six double doublets of H-12, H-13 and H-12′, H-13′ the two vinyl groups and the aromatic singlets of the H-4′ and H-6 protons and the doublets of the H-3, H-4, H-9, H-10, H-6′ and H-8′ protons. These data matched those of a phenanthrene, dehydroeffusol [24,25] and a 9,10-dihydrophenanthrene, effusol [22][23][24] unities. The linkage between the unities was attributed on the basis of 1 H-1 H COSY and HMBC experiments (Fig. 2). ...
... Effususin C (3) was isolated as yellow powder and its IR spectrum showed broad absorption bands for multiple OH groups (3441 cm −1 ). Its 13 C NMR spectrum (Table 1) [24,25], except that the signals for H-6 and H-8 were shifted downfield to δ H 8.17 and 8.44, and C-6 and C-8 were shifted downfield to δ C 129.6 and 131.3, respectively. The aforementioned differences in the NMR data and an upfield-shifted signal for C-7 at δ C 132.4 in 3 instead of δ C 155.2 in dehydroeffusol in the 13 C NMR spectrum indicated that C-7 was not a hydroxyl-bearing sp 2 carbon. ...
... Compounds 1 to 14 were isolated by Shima et al. (1991) and Greca et al. (1996) and all the compounds showed strong antialgal activity. Compounds 4 and 12 were also isolated by Wang Y-G et al. (2012) and showed anxiolytic and sedative activity. compound 15 was isolated by Yang et al. (2007) and no bioactivity were investigated on this compound, compounds 17 and 20 were isolated from Juncus decipiens by Wang Y-G et al. (2012) and both of them showed sedative and anxiolytic activity, compounds 16 and 20 were isolated from the medulla of Juncus decipiens by Wang Y et al. (2014) and showed stronger anxiolytic activity, compound 18 and 19 were isolated from aerial parts of Juncus decipiens by Zhao et al. (2018) and both compounds showed remarkable antifungal activity against six pathogenic fungi, and also showed antibacterial activity against two human pathogenic bacteria, compounds 21 and 22 were isolated by Hu et al. (2022) and showed Estrogenic and anti-neutrophilic inflammatory activity, from compounds 23 to 25 were isolated by Singhuber et al. (2012) Compound 23 showed cytotoxicity and Both 24 and 25 compounds increased GABA induced chloride currents (IGABA) by up to 188 20 (1) and 239 18% (2), independent of the benzodiazepine (BZ) binding site. ...
... Compounds 4 and 12 were also isolated by Wang Y-G et al. (2012) and showed anxiolytic and sedative activity. compound 15 was isolated by Yang et al. (2007) and no bioactivity were investigated on this compound, compounds 17 and 20 were isolated from Juncus decipiens by Wang Y-G et al. (2012) and both of them showed sedative and anxiolytic activity, compounds 16 and 20 were isolated from the medulla of Juncus decipiens by Wang Y et al. (2014) and showed stronger anxiolytic activity, compound 18 and 19 were isolated from aerial parts of Juncus decipiens by Zhao et al. (2018) and both compounds showed remarkable antifungal activity against six pathogenic fungi, and also showed antibacterial activity against two human pathogenic bacteria, compounds 21 and 22 were isolated by Hu et al. (2022) and showed Estrogenic and anti-neutrophilic inflammatory activity, from compounds 23 to 25 were isolated by Singhuber et al. (2012) Compound 23 showed cytotoxicity and Both 24 and 25 compounds increased GABA induced chloride currents (IGABA) by up to 188 20 (1) and 239 18% (2), independent of the benzodiazepine (BZ) binding site. This activity on the GABAA receptor may explain why J. decipiens has traditionally been used as a sedative and anxiolytic agent in Chinese medicine, compounds 26 and 27 were isolated by Ma et al. (2016) and both had a significant inhibitory effect on No production in LPS-activated RAW 264.7 cells, and from compounds 28 to 30 were isolated by Su et al. (2013). ...
Article
Juncus decipiens is a member of the Juncaceae family and has culinary, medicinal, and decorative properties. It is also used in traditional Chinese Medicines for many years that promotes diuresis for strangury and clears out heart fire. This species has recently gained medicinal attention as a source of phenanthrenes, phenolic compounds, glycerides, flavonoids, and cycloartane triterpenes. This plant was also shown to be active, and researchers explored its antioxidant, anti-inflammatory, antialgal, antibacterial, and psychological behaviour-boosting properties. Preliminary research suggests that this species might be used for skin protection and brain disorders if proper clinical trials are conducted. The ethnomedicinal, phytochemistry, biological potencies, dangers, and scopes of Juncus decipiens have been examined in this respect.
... In Chinese Traditional Medicine (TCM), J. effusus is used as a sedative, anxiolytic, antipyretic, and to reduce swelling. Extracts of J. effusus have revealed several cinnamoylglycerides [252,253], cycloartane triterpenoids [255][256][257], phenanthrenes [258][259][260][261][262][263][264]266,267,[269][270][271][272]583,584], and pyrenes [265,268]. Dehydroeffusol, effusol, and juncusol, phenanthrenes isolated from J. effusus, have shown anxiolytic and sedative effects in a mouse model [264,271], likely due to modulation of the gamma-amino butyric acid type A (GABA A ) receptor [272]. ...
... Extracts of J. effusus have revealed several cinnamoylglycerides [252,253], cycloartane triterpenoids [255][256][257], phenanthrenes [258][259][260][261][262][263][264]266,267,[269][270][271][272]583,584], and pyrenes [265,268]. Dehydroeffusol, effusol, and juncusol, phenanthrenes isolated from J. effusus, have shown anxiolytic and sedative effects in a mouse model [264,271], likely due to modulation of the gamma-amino butyric acid type A (GABA A ) receptor [272]. The GABA A modulatory activity may account for the TCM use of J. effusus as a sedative and anxiolytic agent. ...
Article
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Background: Native Americans have had a rich ethnobotanical heritage for treating diseases, ailments, and injuries. Cherokee traditional medicine has provided numerous aromatic and medicinal plants that not only were used by the Cherokee people, but were also adopted for use by European settlers in North America. Methods: The aim of this review was to examine the Cherokee ethnobotanical literature and the published phytochemical investigations on Cherokee medicinal plants and to correlate phytochemical constituents with traditional uses and biological activities. Results: Several Cherokee medicinal plants are still in use today as herbal medicines, including, for example, yarrow (Achillea millefolium), black cohosh (Cimicifuga racemosa), American ginseng (Panax quinquefolius), and blue skullcap (Scutellaria lateriflora). This review presents a summary of the traditional uses, phytochemical constituents, and biological activities of Cherokee aromatic and medicinal plants. Conclusions: The list is not complete, however, as there is still much work needed in phytochemical investigation and pharmacological evaluation of many traditional herbal medicines.
... It would be also interesting to search for dehydrojuncusol in other Juncus species and especially in parts of plant renewable, such as aerial parts. Interestingly, this phenanthrene derivative has been previously isolated from the aerial parts of Juncus species, such as J. acutus (Della Greca et al., 2002) and J. effusus (Wang et al., 2012), increasing its potential for its use in low income countries. ...
... No reports on the antifungal activity of effusol have been provided in the literature so far. The few studies on the biological potential of effusol highlighted cytotoxic, anxiolytic and sedative activities Wang et al. 2012). ...
Thesis
L'approche écologique est une des stratégies de recherche de substances actives. Cette approche porte sur les plantes extrêmophiles, incluant les plantes halophytes et xérophytes, végétaux natifs des biotopes salins et arides. De par leur capacité à subsister dans un environnement contraignant, qui se traduit, entre autres, par l'acquisition d'un système antioxydant puissant, elles se révèlent être des réservoirs en biomolécules, notamment en composés phénoliques. Dans cette étude, nous nous sommes ainsi intéressés à huit plantes halophytes et xérophytes Tunisiennes pouvant avoir des activités biologiques en santé humaine et en santé du végétal. Limonium virgatum (Willd.) Fourr. (Plumbaginaceae), plante halophyte, a montré des activités antioxydantes et antibactériennes intéressantes qui se trouvent respectivement liées à un contenu en polyphénols élevé et à la présence de phénylpropanoïdes. Cirsium scabrum (Poir.) Bonnet & Barratte (Asteraceae), plante xérophyte, a montré une activité cytotoxique selective envers la lignée cancéreuse J774 mettant en avant l'efficacité de triterpènes de type cycloartane ; mais également un pouvoir antibactérien sur des souches de Dermabacter hominis, qui serait lié à la présence de flavones glycosylées. Juncus maritimus Lam. (Juncaceae), plante halophyte, s'est montrée être une source de dérivés phénanthréniques à activités originales. Le juncunol, a montré une activité prometteuse sur une souche de Streptococcus pyogenes résistante à l'amoxicilline. L'effusol actif sur le pathogène de la septoriose du blé (Zymoseptoria tritici), serait stimulé dans les rhizomes de la plante en conditions de salinité élevées. Enfin, le dehydrojuncusol s'est montré être un nouvel inhibiteur de la réplication du virus de l'hépatite C, capable d'agir sur des formes de résistance à certains traitement disponibles sur le marché.
... The polarity of the applied solvent systems is quite variable: some separation steps needed polar solvents including MeOH or EtOAc in high amounts (Behery et al. 2007), while in other cases application of non-polar solvents (e.g. petroleum ether) was sufficient (Wang et al. 2012). The first step of the isolation is the extraction of the plant materials. ...
... s, OE = 6.6 for effusol (4), and OT = 75.5 s, OE = 7.8 for juncusol (2), respectively). Their sedative activity was also confirmed by the decreased locomotion (516.1 for juncusol (2), 498.1 for effusol (4) and 365.6 for diazepam) in the open field test (Wang et al. 2012). In all cases, diazepam was used as positive control (OT = 111.9 ...
Article
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Phenanthrenes represent a relatively small group of aromatic secondary metabolites, which can be divided into three main subgroups (mono-, di-, and triphenanthrenes). Phenanthrenes are reported as an intensively researched field in phytochemistry according to their structural diversity and promising biological activities. Because of their limited occurrence phenanthrenes are considered to be as important taxonomic markers. Juncaceae is a relatively large plant family divided into seven genera of which Juncus and Luzula are the most important ones from phytochemical and pharmacological points of view. To date, almost one hundred natural phenanthrenes have been isolated but only from eight (Juncus acutus, J. effusus, J. inflexus, J. maritimus, J. roemerianus, J. setchuensis, J. subulatus, and Luzula luzuloides) Juncaceae species, including mono-, and diphenanthrenes, and phenanthrene glucosides. Great deal of the isolated compounds are substituted with a vinyl group. This substitution is characteristic exclusively to Juncaceae species. Juncusol (2) was isolated from every investigated species. The richest source of phenanthrenes, as well as the most extensively investigated species is J. effusus. Several isolated compounds possessed different biological activities, e.g. antiproliferative, antimicrobial, anti-inflammatory, antioxidant, spasmolytic, anxiolytic, and antialgal effects. Among them, dehydroeffusol (60) is the most promising one, as it showed antimicrobial, anxiolytic, sedative, spasmolytic, cellular protective and antiproliferative activities. The aim of this review is to summarize the occurrence of phenanthrenes in the family Juncaceae, and give a comprehensive overview of their isolation, structural characteristics and biological activities.
... Although traditional use of plants belonging to the genus Luzula has not been reported yet, several Juncus species (e.g. J. effusus and J. acutus) are used in oriental folk medicine for the treatment of cold, fever, anxiety or insomnia [3][4][5]. ...
... Our results allowed the identification of four phenanthrenes (1-4) substituted with vinyl, hydroxyl, methyl and methoxy groups, one of them (1) is new natural product. The other phenanthrenes (2)(3)(4) were isolated previously only from other Juncaceae species. All of the compounds were isolated for the first time from L. luzuloides. ...
Article
The present study focused on the anti-inflammatory screening of Luzula species native to the Carpathian Basin and bioactivity-guided isolation of compounds of Luzula luzuloides (Lam.) Dandy & Wilmott. The anti-inflammatory properties of extracts with different polarity prepared from Luzula species were determined. Among them, the CH2Cl2-soluble fraction of L. luzuloides possessed strong inhibitory effects on superoxide anion generation (99.39 ± 0.37%) and elastase release (114.22 ± 3.13%) in fMLP/CB-induced human neutrophils at concentration of 10 μg/mL. From this fraction, six compounds (1–6) were isolated by the combination of different chromatographic methods. The structures of the compounds were determined by means of MS, 1D and 2D NMR spectroscopy. The results allowed the identification of the new 1,6-dihydroxy-2-keto-1,7-dimethyl-8-vinyl-1,2-dihydrophenanthrene (1) from the plant, named luzulin A. Chiral HPLC and HPLC-ECD analysis revealed that 1 possesses low enantiomeric excess and TDDFT-ECD calculations afforded the configurational assignment of the separated enantiomers. Three known phenanthrenes [juncuenin B (2), dehydrojuncuenin B (3) and juncusol (4)] and two flavonoids [apigenin (5) and luteolin (6)] were also isolated. The anti-inflammatory activity of the isolated compounds was tested and IC50 values were determined. This was the first time that phenanthrenes were detected in a Luzula species. The oxidative transformation of juncuenin B (3) led to the isolation of its possible biometabolites, namely luzulin A (1), dehydrojuncuenin B (4), and juncuenin D (7). The isolated compounds (1–4) confirm that besides flavonoids, phenanthrenes could also serve as chemotaxonomic markers for Luzula species and prove the close relationship of Juncus and Luzula genus.
... Most of the Juncus species grow exclusively in wetland habitats. In traditional medicine Juncus species are widely used for the treatment of diarrhea, insomnia [10], and as a sedative agent [11]. The infusion of J. acutus fruits and grains and the medulla of J. effusus are used as antipyretic and antiphlogistic agents, as well as treat cold [12]. ...
... Juncusol (2) isolated form J. effusus had photosensitizing activity against several microorganisms [24]. Juncusol (2) was isolated for the first time from J. roemerianus [25], and later it was also found in other Juncaceae species [11,26], but it was detected in the present study for the first time from J. gerardii, J. maritimus and J. tenuis. ...
Article
The main objective of this project was to investigate the antibacterial activity of 19 species (Juncus acutus, J. alpinoarticulatus, J. articulatus, J. compressus, J. conglomeratus, J. effusus, J. filiformis, J. gerardii, J. inflexus, J. maritimus, J. monanthos, J. squarrosus, J. tenuis, J. trifidus, Luzula campestris, L. forsteri, L. luzuloides, L. sudetica and L. sylvatica) belonging to the family Juncaceae against methicillin-resistant S. aureus (MRSA), extended-spectrum β-lactamase (ESBL)-producing C. freundii, E. coli, E. cloacae, K. pneumoniae, and multiresistant A. baumannii and P. aeruginosa. Antibacterial susceptibilities were screened for inhibitory zones and MIC values determined by microdilution method. Among the tested extracts (n = 96) 16 extracts prepared from Juncus species and 3 extracts from Luzula species showed mild to strong inhibitory activities against MRSA strains (inhibition zones = 6.7 mm–14.6 mm; MIC values 9.75–156 μg/mL). It can be concluded that Juncus and Luzula species demonstrated promising anti-MRSA effect, and J. maritimus, J. tenuis and J. gerardii considered worthy of activity-guided phytochemical investigations. The main bioactive constituents of Juncaceae species are phenanthrenes. Four phenanthrenes [juncuenin D (1), juncusol (2), dehydrojuncuenin B (3), and jinflexin B (4)] isolated previously from J. inflexus with anti-MRSA activity were investigated by LC-MS in extracts proved to be active in antimicrobial test.
... Its stem pith has long been used as a sedative, anxiolytic, antipyretic and diuretic agent for the treatment of fidgetiness, insomnia and edema in traditional Chinese medicine [1,2]. Previous phytochemical investigations on this genus have reported the existence of secondary metabolites such as phenanthrenoids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17], dihydrodibenzoxepins [13,18], benzocoumarins [19], phenylpropane glycerides [6,20,21], flavonoids [7], triterpenes [22], and phenolic acid derivatives [1]. Phenanthrenoids are characteristic constituents of the genus Juncus, exhibiting a wide range of biological activities like anti-algal [3,[8][9][10]12,13,15], cytotoxic [1,2], antitumor [17], anti-inflammatory [2,4], anxiolytic [5,14], and antioxidant [7] activities. ...
... Previous phytochemical investigations on this genus have reported the existence of secondary metabolites such as phenanthrenoids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17], dihydrodibenzoxepins [13,18], benzocoumarins [19], phenylpropane glycerides [6,20,21], flavonoids [7], triterpenes [22], and phenolic acid derivatives [1]. Phenanthrenoids are characteristic constituents of the genus Juncus, exhibiting a wide range of biological activities like anti-algal [3,[8][9][10]12,13,15], cytotoxic [1,2], antitumor [17], anti-inflammatory [2,4], anxiolytic [5,14], and antioxidant [7] activities. Phenanthrenoid dimers were previously reported from this genus, however, their number is still few [2,[7][8][9]12]. ...
Article
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Two new phenanthrenoid dimers, named dijuncuenins A (1) and B (2), were isolated from the ethanolic extract of the whole plant of Juncus effusus. Their structures were determined by 1D and 2D NMR spectroscopic analysis and mass spectrometry. The plausible biosynthetic pathways of compounds 1 and 2 were proposed.
... In Japan and other far-east countries, J. effuses was used as sedative, antipyretic and antiphlogistic agent (Shima et al. 1991). Phenanthrenoids, flavonoids, cycloartane triterpenes, rasane dietrpenes, phenolics and steroids from this herb have been characterized (EI-Shamy et al. 2015), and the phenanthrenoid compounds were documented as the major biologically active compounds with the anti-anxiolytic and sedative (Liao et al. 2011;Wang et al. 2012), anti-inflammatory (Behery et al. 2007), anti-cancer (Della Greca et al. 1993Greca et al. , 1995Lam et al. 1977;Lee et al. 2009;Su et al. 2013), cellular protective (Park et al. 2014), and anti-algal activity (Della Greca et al. 2004). As a part of our ongoing work on the bioactive compounds from Chinese medicinal herbs, the chemical and pharmacological investigations on J. effuses was carried out. ...
... The crude extract was further fractionated and purified over columns of silica gel, Sephadex LH-20 and Chromatorex ODS to give two new compounds (1 and 2), as well as 15 known compounds (3-17). The known ones were identified as effususol A (3) (Ishiuchi et al. 2015), effusol (4) (Della Greca et al. 1992), dehydroeffusol (5) (Shima et al. 1991), 2, 7-dihydroxy-1-methyl-5-aldehyde-9, 10-dihydrophenanthrene (6) (Wang et al. 2012), dehydroeffusal (7) (Shima et al. 1991), juncuenin F (8) (Su et al. 2013), 2, 7-dihydroxy-5-hydroxymethyl-1-methyl-9, 10-dihydrophenathrene (9) (Della Greca et al. 2004), 5-hydroxymethyl-1-methylphenanthrene-2, 7-diol (10) (Yang et al. 2007), 2, 7-dihydroxy-1,8-dimethyl-5-vinyl-9,10-dihydrophenanthrene (11) (Della Greca et al. 1992), juncusol (12) (Della Greca et al. 1992), dehydrojuncusol (13) (Della Greca et al. 2002), dehydrojuncuenin E (14) (Su et al. 2013), juncuenin G (15) (Su et al. 2013), dehydrojuncuenin D (16) (Su et al. 2013) and 1-methylpyrene-2, 7-diol (17) (Yang et al. 2007) by the spectroscopic evidences and comparing with previous literature data (Fig. 1). ...
Article
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Bioactivity guided phytochemical investigation of the ethanol extract of the medullae of Juncus effusus resulted in the isolation of two new phenanthrenes, 8-hydroxymethyl-2-hydroxyl-1-methyl-5-vinyl-9,10-dihydrophenanthrene (1), and 5-(1-methoxyethyl)-1-methyl-phenanthren-2,7-diol (2) together with 15 known phenanthrenoids (3-17). The chemical structures of 1 and 2 were established by a combination of spectroscopic techniques. Compounds 1-15 and 17 were evaluated for their cytotoxic activities against five human cancer cell lines (SHSY-5Y, SMMC-7721, HepG-2, Hela and MCF-7) by CCK-8 assay, and their anti-inflammatory activities were also evaluated by inhibition on NO production in LPS-activated murine macrophage RAW 264.7 cells.
... Recent studies have demonstrated that this group of secondary metabolites have a wide range of bioactivities, including anti-tumour, anti-bacterial, anti-viral and anti-inflammatory effects, and hence have potential medical applications for a diversity of ailments (e.g. El-Shamy et al., 2015;Ma et al., 2015;Wang et al., 2012). These metabolites are also now being investigated to explore their potential to be developed into new biopesticides to enable more sustainable farming practices in the future (Bakacsy et al., 2022). ...
Article
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We present a genome assembly from a Juncus effusus (soft rush; Tracheophyta; Magnoliopsida; Poales; Juncaceae). The genome sequence is 242.9 megabases in span. Most of the assembly is scaffolded into 21 chromosomal pseudomolecules. The mitochondrial genome is 519.0 kilobases long, while the plastid genome is 175.1 kilobases long.
... As the results about chemical compositions of J. effusus, one new phenanthrenes, Junfusol B (2), together with seventeen known compounds, Junfusol A (1) (Ishiuchi et al. 2015), effusol (3) (Shima et al. 1991), 2,7-Dihydroxy-1,8-dimethyl-5-vinyl-9,10-dihydrophenanthrene (4) (Shima et al. 1991;Greca et al. 1993), juncusol (5) (Shima et al. 1991), 2-Hydroxy-7-(hydroxymethyl)-1-methyl-5-vinyl-9,10-dihydrophenanthrene (6) (Greca et al. 1997), 2,7-dihydroxy-1-methyl-5-aldehyde-9,10-dihydrophenanthrene (7) (Wang et al. 2012) , juncuenin F (8) (Greca et al. 1993), dehydroeffusol (9) (Hanawa et al. 2002), dehydrojuncusol (10) (Behery et al. 2013), dehydoreffusal (11) (Shima et al. 1991), desvinyljuncusol (12) (Boger et al. 1985), 1-methylpyrene-2,7-diol (13) (Fenz and Galensa 1989), 1-O-trans-p-coumaroylglycerol (14); 1-O-cis-p-coumaroylglycerol (15) (Fenz and Galensa 1989;Jin et al. 1996), 1,3-O-trans-diferuloylglycerol (16); 1,3-O-cisdiferuloylglycerol (17) (Shimomura et al. 1987), and 5,7-dimethoxychroman-4-one (18) (Shaikh et al. 2012) were identified ( Figure 1). ...
Article
Juncus effusus L. (J. effusus) is a Traditional Chinese Medicine (TCM) that has long been used for dealing with gynaecological disorders, such as relieving insomnia, preventing tinnitus, reducing edema with diuretic effect. In our course of evidence-based medical research focused on this herb, one new phenanthrene, Junfusol B (2), together with seventeen known compounds were isolated and identified. All the structures of these compounds were elucidated by spectroscopic methods. The absolute stereochemistry of compounds 1 and 2 was further determined by comparing their calculated and experimental Electronic Circular Dichroism (ECD) spectra and optical rotation (OR) values. The isolates were evaluated for their estrogenic and anti-inflammatory activities which were considered as relevant etiological factors of insomnia, tinnitus and edema in the ancient TCM theory. The results revealed that most of the obtained phenanthrenes in this work were found exerting agonistic effects on estrogen receptor. This is the first report to declare the exact estrogen-regulating potential among this type of compounds from J. effusus. Moreover, phenanthrenes 3 − 7 exhibited significant inhibitions on superoxide anion generation and elastase release in fMLP/CB-induced human neutrophilic inflammation model. J. effusus may be developed as a complementary agent utilized in menopausal multiple syndromes.
... The three-dimensional structure of GABA receptor in complex diazepam was obtained from Protein Data Bank (PDB ID = 6X3X). Energy minimization of the ligand, preparation of structures of the downloaded enzymes, and active site identification were carried out according to a previously reported procedure [18][19][20]. ...
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Traditionally, Diospyros lotus Linn is used for insomnia and other associated disorders. Insomnia is a worldwide disorder with different etiology which is treated with different synthetic medicine associated with addiction. Natural products are generally devoid of such addition with good efficacy. Current research was conducted to evaluate the sedative and hypnotic effects of dimeric naphthoquinones such as dinaphthodiospyrol A (1), dinaphthodiospyrol B (2), dinaphthodiospyrol C (3), dinaphthodiospyrol D (4), dinaphthodiospyrol E (5) and dinaphthodiospyrol F (6) isolated from the chloroform fractions of D. lotus. The sedative and hypnotic effects at the dose of 5 and 10 mg/kg (each compound) were assessed through open field and phenobarbital induced sleep test, respectively. In the case of open field test the administration of tested compounds significantly hindered the movement of animals, while in case of hypnotic effect the tested samples significantly improved the onset and duration of sleep as compared to control. The overall effects were in a dose dependent manner. The compounds were also assessed for acute toxicity, but no toxicity was observed. In this regard, our research triumphantly announced the strong chemical base for the folkloric values of the plant with their fringe benefits and implemented a platform for further aspects of mechanistic and clinical studies. A possible mechanism of in vivo inhibition was studied by using docking simulations on GABA receptors. Binding orientations and types of interactions revealed that a possible mechanism behind these pharmacological actions might be interaction with GABA receptors.
... As part of our ongoing research program, we describe here the isolation and structure determination of four new [maritins A-D (1-4)] and seven known (5)(6)(7)(8)(9)(10)(11) phenanthrenes from the methanol extract of J. maritimus. The antiproliferative activity of the isolated phenanthrenes was investigated on seven human cancer cell lines (HeLa, HTM-26, T-47D, A2780, A2780cis, MCF-7, KCR) and one normal cell line (MRC-5). ...
Article
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Juncaceae family represents an abundant source of phenanthrenes. In continuation of our work aiming at the isolation of biologically active compounds from Juncaceae species, Juncus maritimus Lam. was subjected to phytochemical and pharmacological investigations. The isolation process was carried out by using combined extraction and chromatographic methods. The structures of the obtained chemical compounds were elucidated by spectroscopic analysis, including HRESIMS, 1D (1H, 13C-JMOD), and 2D (1H-1H-COSY, HSQC, HMBC, NOESY) NMR spectra. Four new [maritins A–D (1–4)] and seven known phenanthrenes (5–11) were isolated from the plant, of which two (4 and 11) are phenanthrene dimers composed of effusol monomers. Maritin C (3) has an unusual 4,5-ethanophenanthrene skeleton most likely produced by biosynthetic incorporation of a vinyl group into a cyclohexadiene ring. Compounds 1–11 were tested for their antiproliferative activity on seven human tumor cell lines (HeLa, HTM-26, T-47D, A2780, A2780cis, MCF-7, KCR) and one normal cell line (MRC-5) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The dimeric phenanthrenes showed strong antiproliferative activity against T-47D cells with IC50 values of 9.1 and 6.2 µM, respectively.
... Juncusol was isolated previously from numerous Juncus species (J. acutus, J. effusus, J. inflexus, J. roemerianus, J. setchuensis, and J. subulatus) [9,[30][31][32][33][34]. Similarly to juncusol, effusol is also a ubiquitous phenanthrene in Juncus species, as it was isolated from J. acutus, J. atratus, J. compressus, J. effusus, J. maritimus, J. setchuensis, and J. subulatus [6,7,30,[33][34][35][36]. Moreover, 2,7-Dihydroxy-1,8-dimethyl-5-vinyl-9,10-dihydrophenanthrene was identified before from J. acutus and J. effusus [19,28,29]. ...
Article
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The occurrence of phenanthrenes is limited in nature, with such compounds identified only in some plant families. Phenanthrenes were described to have a wide range of pharmacological activities, and numerous research programs have targeted semisynthetic derivatives of the phenanthrene skeleton. The aims of this study were the phytochemical investigation of Juncus tenuis, focusing on the isolation of phenanthrenes, and the preparation of semisynthetic derivatives of the isolated compounds. From the methanolic extract of J. tenuis, three phenanthrenes (juncusol, effusol, and 2,7-dihydroxy-1,8-dimethyl-5-vinyl-9,10-dihydrophenanthrene) were isolated. Juncusol and effusol were transformed by hypervalent iodine(III) reagent, using a diversity-oriented approach. Four racemic semisynthetic compounds possessing an alkyl-substituted p-quinol ring (1–4) were produced. Isolation and purification of the compounds were carried out by different chromatographic techniques, and their structures were elucidated by means of 1D and 2D NMR, and HRMS spectroscopic methods. The isolated secondary metabolites and their semisynthetic analogues were tested on seven human tumor cell lines (A2780, A2780cis, KCR, MCF-7, HeLa, HTB-26, and T47D) and on one normal cell line (MRC-5), using the MTT assay. The effusol derivative 3, substituted with two methoxy groups, showed promising antiproliferative activity on MCF-7, T47D, and A2780 cell lines with IC50 values of 5.8, 7.0, and 8.6 µM, respectively.
... The 1 H and 13 C NMR data showed the presence an aldehyde function with the corresponding carbon at δC 193.5 ppm (CH) and a singlet proton at δH 10.07 ppm. As previously reported in literature [28][29][30], the aldehyde function was located on C-5. This was confirmed by the HMBC correlations from H-12 (δH 10.07) to C-6 (δC 127.2). ...
Article
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Phenanthrenoids have been widely described, in the Juncaceae family, for their biological properties such as antitumor, anxiolytic, anti‐microbial, spasmolytic, and antiinflammatory activities. The Juncaceae family is known to contain a large variety of phenanthrenoids possessing especially anti‐inflammatory and cytotoxic properties. Luzula sylvatica, a Juncaceae species, is widely present in the Auvergne region of France, but has never been studied neither for its phytochemical profile nor for its biological properties. We investigated the phytochemical profile and evaluated the potential anti‐inflammatory activities of L. sylvatica aerial parts extracts. A bioassay‐guided fractionation was carried out to identify the most active fractions. Nine compounds were isolated, one coumarin 1 and eight phenanthrene derivatives (2–9), including four new compounds (4, 5, 8 and 9), from n‐hexane and CH2Cl2, fractions. Their structures were established by HRESIMS, 1D and 2D NMR experiments. The biological properties, especially the anti‐inflammatory/antioxidant activities (ROS production) and antiproliferative activity on THP‐1, a monocytic leukemia cell line, of each compound, were evaluated. Three phenanthrene derivatives 4, 6, and 7 showed very promising antiproliferative activities.
... It also would be interesting to search for dehydrojuncusol in other Juncus species and especially in parts of the plant that are renewable, such as aerial parts. Interestingly, this phenanthrene derivative has been previously isolated from the aerial parts of Juncus species, such as Juncus acutus (36) and Juncus effusus (37), increasing its potential for use in low income countries. ...
Article
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Tens of millions of people are infected with hepatitis C virus (HCV) worldwide. Recently marketed direct-acting antivirals (DAAs) targeting HCV proteins have enhanced the efficacy of treatment. However, due to its high cost, this new therapy is not accessible to the vast majority of infected patients. Furthermore, treatment failures have also been reported due to the appearance of viral resistance. Here, we report on the identification of a new HCV inhibitor, dehydrojuncusol, that targets HCV NS5A and is able to inhibit RNA replication of replicons harboring resistance mutations to anti-NS5A DAAs used in current therapy. Dehydrojuncusol is a natural compound isolated from Juncus maritimus , a halophilic plant species that is very common in coastlines worldwide. This molecule might serve as a lead for the development of a new therapy that is more accessible to hepatitis C patients in the future.
... It also would be interesting to search for dehydrojuncusol in other Juncus species and especially in parts of the plant that are renewable, such as aerial parts. Interestingly, this phenanthrene derivative has been previously isolated from the aerial parts of Juncus species, such as Juncus acutus (36) and Juncus effusus (37), increasing its potential for use in low income countries. ...
Preprint
Recent emergence of direct acting antivirals (DAAs) targeting hepatitis C virus (HCV) proteins has considerably enhanced the success of antiviral therapy. However, the appearance of DAA resistant-associated variants is a cause of treatment failure, and the high cost of DAAs renders the therapy not accessible in countries with inadequate medical infrastructures. Therefore, search for new inhibitors and with lower cost of production should be pursued. In this context, crude extract of Juncus maritimus Lam. was shown to exhibit high antiviral activity against HCV in cell culture. Bio-guided fractionation allowed isolating and identifying the active compound, dehydrojuncusol. A time-of-addition assay showed that dehydrojuncusol significantly inhibited HCV infection when added after virus inoculation of HCV genotype 2a (EC 50 = 1.35 µM). This antiviral activity was confirmed with a HCV subgenomic replicon and no effect on HCV pseudoparticle entry was observed. Antiviral activity of dehydrojuncusol was also demonstrated in primary human hepatocytes. No in vitro toxicity was observed at active concentrations. Dehydrojuncusol is also efficient on HCV genotype 3a and can be used in combination with sofosbuvir. Interestingly, dehydrojuncusol was able to inhibit replication of two frequent daclatasvir resistant mutants (L31M or Y93H in NS5A). Finally, resistant mutants to dehydrojuncusol were obtained and showed that HCV NS5A protein is the target of the molecule. In conclusion, dehydrojuncusol, a natural compound extracted from J. maritimus , inhibits infection of different HCV genotypes by targeting NS5A protein and is active against HCV resistant variants frequently found in patients with treatment failure. Importance Tens of millions of people are infected with hepatitis C virus (HCV) worldwide. Recently marketed direct acting antivirals (DAAs) targeting HCV proteins have enhanced the efficacy of the treatment. However, due to its high cost, this new therapy is not accessible to the vast majority of infected patients. Furthermore, treatment failures have also been reported due to appearance of viral resistance. Here we report on the identification of a new HCV inhibitor, dehydrojuncusol that targets HCV NS5A and is able to inhibit replication of replicons harboring resistance mutations to anti-NS5A DAAs used in current therapy. Dehydrojuncusol is a natural compound isolated from Juncus maritimus , a halophilic plant species very common in the coastlines worldwide. This molecule might serve as a lead for the development of new therapy more accessible to hepatitis C patients in the future.
... Accumulating reports have been published on the anxiolytic activities of natural smallmolecule phenols (NSMPs), including, but not limited to, honokiol [5], paeonol [6], quercetin [7], carvacrol [8], kaempferol [9], and danshensu [10]. Our research group is focusing on anxiolytic natural products, and some anxiolytic natural phenols were found, including juncusol [11,12], effusol [13], and orcinol [14]. Initial reviews of the literature and our findings triggered us to consider other NSMPs and their mechanism of action. ...
Article
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Natural small-molecule phenols (NSMPs) share some bioactivities. The anxiolytic activity of NSMPs is attracting attention in the scientific community. This paper provides data supporting the hypothesis that NSMPs are generally anxiolytic. The anxiolytic activities of seven simple phenols, including phloroglucinol, eugenol, protocatechuic aldehyde, vanillin, thymol, ferulic acid, and caffeic acid, were assayed with the elevated plus maze (EPM) test in mice. The oral doses were 5, 10 and 20 mg/kg, except for phloroglucinol for which the doses were 2.5, 5 and 10 mg/kg. All tested phenols had anxiolytic activity in mice. The phenolic hydroxyl group in 4-hydroxycinnamic acid (4-OH CA) was essential for the anxiolytic activity in the EPM test in mice and rats compared to 4-chlorocinnamic acid (4-Cl CA). The in vivo spike recording of rats’ hippocampal neurons also showed significant differences between 4-OH CA and 4-Cl CA. Behavioral and neuronal spike recording results converged to indicate the hippocampal CA1 region might be a part of the anxiolytic pathways of 4-OH CA. Therefore, our study provides further experimental data supporting NSMPs sharing anxiolytic activity, which may have general implications for phytotherapy because small phenols occur extensively in herbal medicines.
... No reports on the antifungal activity of effusol have been provided in the literature so far. The few studies on the biological potential of effusol highlighted cytotoxic, anxiolytic, and sedative activities (Ishiuchi et al. 2015;Wang et al. 2012). Moreover, no reports exist in the literature on the antifungal activity against Z. tritici for J. maritimus, neither for the Juncus genus. ...
Article
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Zymoseptoria tritici, responsible for Septoria tritici blotch, is the most important pathogen of wheat. The control of this parasite relies mainly on synthetic fungicides, but their use is increasingly controversial and searching for alternative management strategies is encouraged. In this context, the biocontrol potential of crude methanolic extracts of eight extremophile plant species from Tunisia, including three xerophytes and five halophytes, against Z. tritici was assessed. Only the extract of Juncus maritimus rhizomes showed significant in vitro antifungal activity. In extremophile plants, the production of secondary metabolites is often influenced by abiotic conditions. Thus, we collected several samples of J. maritimus rhizomes at different vegetative stages, at different periods, and from different substrates to compare their antifungal activities. Our results suggest that the plant environment, especially the substrate of the soil, should be taken into account to identify great sources of natural antifungal products. From the most active sample, a 9,10-dehydrophenanthrene derivative, effusol, absent from other J. maritimus rhizomes extracts, was purified. This product showed a strong antifungal activity against the pathogen, with a minimal inhibitory concentration of 19 μg mL(-1) and an half-maximal inhibitory concentration of 9.98 μg mL(-1). This phenanthrene derivative could be a promising biocontrol molecule against Z. tritici.
... These receptors occurring at postsynaptic membranes bind to GABA, which leads to subdued neuronal excitability [24]. Additionally, the anxiolytic action of benzodiazepines can be ascribed to direct activation of glycine synapses in the brain [25]. Studies have shown that benzodiazepines bind to the g subunit of the GABA A receptor, implicating allosteric modification of the receptor and subsequent enhancement in activity [24]. ...
... 13 Compounds containing the phenanthrene nucleus have displayed a wide range of biological activities including anticancer, [14][15][16] antimicrobial, 17,18 anxiolytic and sedative activities. 19 In nature, the aromatic rings of the phenanthrene nucleus are often decorated with oxygenated substituents -typically hydroxy methoxy or methylenedioxy groups. One subgroup of phenanthrene natural products are the phenanthrene alkaloids, (typified by Nmethyl seco-glaucine, 10). ...
Article
Oxa-Pictet-Spengler cyclization and microwave-assisted C-H arylation have been implemented as key steps in the synthesis of new isochroman heterocycles containing a 4,5,6a,7-tetrahydrodibenzo[de,g]chromene motif. These isochromans may be easily transformed to phenanthrene alkaloids via acidic cleavage of the isochroman ring and standard synthetic manipulations thereafter. The route described is attractive in that it provides access to two biologically interesting scaffolds in simple and high yielding synthetic steps.
... Thus, compound 6 was determined to be ethyl 5-O-trans-feruloyl-α-arabinofuranoside. The structure of the compound 7 was identified as 2,7-dihydroxy-1-methyl-5-aldehyde-9,10-dihydrophenanthrene by NMR and HR-ESIMS and comparing its measured spectroscopic data with literature values [11]. Compounds 3, 4, and 6 are ethylated derivatives. ...
Article
A chemical investigation of the EtOAc-soluble fraction from the ethanol extract of the medullae of Juncus effusus led to the isolation of three new 9,10-dihydrophenanthrenes, juncuenins E-G (1-3); two new phenanthrenes, dehydrojuncuenins D-E (4-5); one new feruloylated glycoside (6); and one known 9,10-dihydrophenanthrene (7). The structures of these compounds were determined by analyzing their spectroscopic data. Metabolites 1-4 and 7 were further evaluated for their in vitro cytotoxic activities against seven human cancer lines (A549, MCF-7, BEL-7402, HeLa, COLO205, BGC-823, and SK-OV-3). Among them, compound 1 exhibited weak cytotoxicity against MCF-7 and HeLa cell lines. Compound 7 showed moderate cytotoxicity against MCF-7 and HeLa cell lines, with IC50 values of 9.17 and 19.6 µM, respectively.
Chapter
A variety of plants are good sources of therapeutic agents, mainly due to their secondary metabolites, chemical compounds formed from the conversion of light energy. Among these metabolites are the diterpenes, a group of structurally diverse molecules widely distributed in nature. Diterpenes exhibit a broad spectrum of biological activities and have been extensively studied due to promising results in their antitumor effects. Breast cancer is one of the most common cancer types found worldwide, varying from mild and potentially curable to incurable manifestations using the treatments available. Therefore, the search for new drugs is urgent and necessary. This chapter provides a literature update and a review of the antibreast cancer effects of diterpenes from plants, based on published studies indexed in the main databases during 2015–20. The structure, mechanism of action, molecular targets, and in silico, in vitro, and in vivo effects are presented.
Chapter
Stereoselective O-glycosylation is essential in order for achieving facile assembly of biologically relevant oligosaccharides. Numerous studies have been conducted to develop glycosylation reactions, whose efficiency and selectivity are influenced by a variety of factors including leaving groups, activators, protective groups, and reaction conditions. Although combined use of carefully designed donors enables synthesis of complex oligosaccharides, synthetic schemes are usually complicated, because formation of 1,2-cis and -trans glycosides requires distinct donors. Synthesis of oligopeptides is simpler, as it can be accomplished by unified strategies that employ either Fmoc- or Boc-protected amino acid components. Accordingly, establishment of a strategy to obtain both anomers from a single glycosyl donor is desired in order for simplifying oligosaccharide synthesis. In this review, we would like to present the recent advances of the stereoselective bimodal glycosylations for the synthesis of various naturally occurring glucans having various linkages and branches. Among the various approaches, we will introduce that our recent bimodal donors equipped with C2-o-TsNHbenzyl ether (TAB) not only for glucotype glycosylation1 such as glucosylation and galactosylation, but also for manno-type glycosylation2 can be transformed to both anomers by switching reaction conditions. We also would like to show the applications to stereocontrolled assembly of various types of glucans which are the most abundant and the one of the biologically important natural products and are widely present in fungal, bacterial, mammalian, and plant classes. The achievement of the synthesis of all possible types of glucans, such as linear and branched α-, β- as well as mixed α,β-glucans with various linkage positions, was also explained in detail.
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In recent years, traditional Chinese medicines and active natural ingredients have been increasingly recognized for their medication effect worldwide. Phenanthrene derivatives, one of the main active ingredients in many Chinese herbal medicines such as Dendrobium, Bletilla, Juncaceae, have achieved great attention by botanists, biologists, and pharmacists due to their chemical structural diversity and practical biological activities. Nearly 200 natural phenanthrene compounds found from natural Chinese medicine plants are discussed in this review. Plants in the Orchidaceae, Juncaceae, Dioscoreaceae, and Lauraceae families, among others, produce phenanthrene chemicals. Furthermore, their medicinal effects and mechanisms of action are summarized, emphasizing anti-inflammatory, anti-bacterial, anti-cancer, and anti-oxidative activities. It provides a foundation for further exploring and developing new drugs with phenanthrene compounds as the essential core structure.
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Anxiety is a disorder with known etiology and clinical symptoms which is managed by combination therapy or the use of complementary and alternative medicine (CAM), such as psychopharmacotherapy, cognitive behavioral therapy, and herbal medicine. The approach of scientists is to identify natural anxiolytics, based on their active components and their mechanism of action. So far, several medicinal plants have been identified and their effective components have been isolated and characterized as having cellular and molecular targets to the central nervous system (CNS). Despite the progress made in identification, application and drug interaction issues of such products, further studies should be planned to minimize their side effects and enhance their efficiency and specificity for a given health condition. The use of natural anxiolytics, either alone or in combination with other remedies can be improved by managing the preparation protocols, the route and the form of administration. In this context, natural drinks such as coffee with high levels of caffeine may exacerbate the clinical symptoms of anxiety. On the other hands, theanine (present in tea leaves) can alleviate the symptoms of the disorder. The current information available on traditional medicine and pharmacognosy is promising for formulation of nutraceuticals more specifically, with highest efficiency for prevention and treatment of anxiety. This review article attempts to introduce major herbs/plants recognized for their anti-anxiety effects and explain the feasibility for their specific application. The methods for the extract preparation and optimum condition for using such materials as traditional medicine or for their use in new formulations as nutraceuticals is suggested. The review also includes information about anxiety disorders, etiology, symptoms, types, neurobiology and different approaches to ameliorate anxiety conditions.
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The plants of Orchidaceae are widely distributed in the world, 47 species of which have been used as folk medicines with a long history. The tubers and stems of them exhibit diverse efficacy, including clearing heat and resolving toxin, moistening lung and relieving cough and promoting blood circulation. Since dihydrophenanthrenes were responsible for the medical purposes, the characteristic skeletons, pharmacological effects and clinical applications of dihydrophenanthrenes were summarized in this review, so as to provide a theoretical basis for the comprehensive study, development and application of DPs from medicinal plants of Orchidaceae.
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Dehydroeffusol, a phenanthrene isolated from Juncus effusus, is a Chinese medicine. To explore an efficacy of dehydroeffusol administration for prevention and cure of Alzheimer’s disease, here we examined the effect of dehydroeffusol on amyloid β1-42 (Aβ1-42)-mediated hippocampal neurodegeneration. Dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 6 days and then human Aβ1-42 was injected intracerebroventricularly followed by oral administration for 12 days. Neurodegeneration in the dentate granule cell layer, which was determined 2 weeks after Aβ1-42 injection, was rescued by dehydroeffusol administration. Aβ staining (uptake) was not reduced in the dentate granule cell layer by pre-administration of dehydroeffusol for 6 days, while increase in intracellular Zn2+ induced with Aβ1-42 was reduced, suggesting that pre-administration of dehydroeffusol prior to Aβ1-42 injection is effective for Aβ1-42-mediated neurodegeneration that was linked with intracellular Zn2+ toxicity. As a matter of fact, pre-administration of dehydroeffusol rescued Aβ1-42-mediated neurodegeneration. Interestingly, pre-administration of dehydroeffusol increased synthesis of metallothioneins, intracellular Zn2+-binding proteins, in the dentate granule cell layer, which can capture Zn2+ from Zn-Aβ1-42 complexes. The present study indicates that pre-administration of dehydroeffusol protects Aβ1-42-mediated neurodegeneration in the hippocampus by reducing intracellular Zn2+ toxicity, which is linked with induced synthesis of metallothioneins. Dehydroeffusol, a novel inducer of metallothioneins, may protect Aβ1-42-induced pathogenesis in Alzheimer’s disease.
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Species in the Juncaceae accumulate different types of secondary metabolites, among them phenanthrenes and 9,10-dihydrophenanthrenes in substantial amounts. These compounds have chemotaxonomic significance and also possess interesting pharmacological activities. The present study has focused on the isolation, structure determination, and pharmacological investigation of phenanthrenes from Juncus gerardii. Twenty-six compounds, including 23 phenanthrenes, have been isolated from a methanol extract of this plant. Twelve compounds, the phenanthrenes gerardiins A–L (1–12), were obtained as new natural products. Eleven phenanthrenes [effusol (13), dehydroeffusol (14), effususin A (15), compressin A, 7-hydroxy-2-methoxy-1-methyl-5-vinyl-9,10-dihydrophenanthrene, juncusol, 2-hydroxy-7-hydroxymethyl-1-methyl-5-vinyl-9,10-dihydrophenanthrene, 2,7-dihydroxy-5-formyl-1-methyl-9,10-dihydrophenanthrene, effususol A, 2,7-dihydroxy-5-hydroxymethyl-1-methyl-9,10-dihydrophenanthrene, and jinflexin C], 1-O-p-coumaroyl-3-O-feruloyl-glycerol, and the flavones apigenin and luteolin were isolated for the first time from this plant. The cytotoxicity of the 23 isolated phenanthrenes in both mouse (4T1) and human (MDA-MB-231) triple-negative breast cancer cells and in a nontumor (D3, human cerebral microvascular endothelial) cell line was tested using an MTT viability assay. The results obtained showed that the dimeric compounds gerardiins I (9), J (10), K (11), and L (12), derived biogenetically from effusol and dehydroeffusol, were cytotoxic to both tumor and nontumor cell lines, while the monomeric compounds exerted no or very low cytotoxicity. Impedance measurements were consistent with the results of the MTT assays performed.
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Amyloid β (Aβ) peptides produced from the amyloid precursor protein, a transmembrane protein, are neurotoxic and blocking the neurotoxicity may lead to prevention of Alzheimer’s disease (AD). Here we tested whether Aβ25–35-induced cognitive decline is rescued by treatment with dehydroeffusol, a phenanthrene isolated from Chinese medicine Juncus effusus. Dehydroeffusol (5 ~ 15 mg/kg body weight) was orally administered to mice for 6 days and Aβ25–35 (2 mM) was injected at the rate of 1 μl/min for 3 min into the lateral ventricle. Y-maze test was performed after dehydroeffusol administration for 12 days. Aβ25–35 impaired learning and memory in the test, while the impairment was dose-dependently rescued by dehydroeffusol administration. The present study indicates that treatment with dehydroeffusol is effective for rescuing Aβ25–35-induced cognitive decline.
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Exposure to corticosterone attenuates hippocampal CA1 long-term potentiation (LTP) via intracellular Zn²⁺ dysregulation. Here we report that effusol, a phenanthrene isolated from Chinese medicine Juncus effusus, rescues CA1 LTP attenuated by corticosterone. In vivo microdialysis experiment indicated that both increases in extracellular glutamate induced under perfusion with corticosterone and high K⁺ are suppressed in the hippocampus by co-perfusion with effusol. Because corticosterone and high K⁺ also increase extracellular Zn²⁺ level, followed by intracellular Zn²⁺ dysregulation, the effect of effusol on both the increases was examined in brain slice experiments. Effusol did not suppress increase in extracellular Zn²⁺ in the hippocampal CA1 of brain slices bathed in corticosterone, but suppressed increase in intracellular Zn²⁺, which may be linked with suppressing the increase in extracellular glutamate in vivo. In vivo CA1 LTP was attenuated under perfusion with corticosterone prior to LTP induction, while the attenuation was rescued by co-perfusion with effusol, suggesting that the rescuing effect of effusol is due to suppressing the increase in intracellular Zn²⁺ in CA1 pyramidal cells. The present study indicates that CA1 LTP attenuated by corticosterone is canceled by effusol, which rescues intracellular Zn²⁺ dysregulation via suppressing extracellular glutamate accumulation. It is likely that effusol defends the hippocampal function against stress-induced cognitive decline.
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The chemistry of palladium complexes has no limits. Many domino processes (even multicomponent) are continuously appearing in the literature. Carbocyclic and heterocyclic molecules are efficiently prepared under the atom-economy principle using the smallest amount of the catalyst. The importance of the applications in many scientific areas of all of these cyclic skeletons made this general methodology much more attractive.
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Organic anion transporters 1 (OAT1) and 3 (OAT3) play important roles in the renal elimination of a range of substrate molecules. Little is known about natural products that can modulate OAT1 and OAT3 activities. The medullae of Juncus effusus is often used for the treatment of dysuria in traditional Chinese medicine. To study the interactions of phytochemicals in J. effusus with human OAT1 and OAT3, a bioactivity guided phytochemical investigation led to seven new phenanthrenoids along with nine known compounds, including eight phenanthrenoids and a benzophenone from the dichloromethane soluble fraction of a methanol extract of the medullae of J. effusus. The structures were established by physical data analysis, including high-resolution electrospray ionization mass spectrometry and 1D and 2D NMR. The compounds were evaluated for inhibition of OAT1 and OAT3 in vitro. Compounds 10 and 16 were inhibitors for OAT1, and compounds 1-3, 10, and 16 were inhibitors for OAT3 with IC 50 values less than 5.0 μM. Dihydrophenanthrene 1 markedly altered the pharmacokinetic parameters of the diuretic drug furosemide, a known substrate of both OAT1 and OAT3, in vivo. © 2019 American Chemical Society and American Society of Pharmacognosy.
Article
Fu‐Ke‐Zai‐Zao pills, the famous traditional Chinese medicine formula, composed of 42 medicinal herbs, have been widely used to treat various gynecological diseases. However, the chemical constituents and metabolic profiling of Fu‐Ke‐Zai‐Zao pills remain largely unknown, which hampers improvement of the quality control and pharmacological elucidation of this formula. In the present study, a sensitive and selective ultra‐performance liquid chromatography coupled with quadrupole‐time‐of‐flight mass spectrometry method was developed to separate and identify the comprehensive chemical constituents of Fu‐Ke‐Zai‐Zao pills. As the results, a total of 83 compounds were identified, including phenylpropionic acids, flavonoids, terpenoids, triterpene saponins, and phthalides, and 81 compounds were first reported in Fu‐Ke‐Zai‐Zao pills. Moreover, the absorbed components and metabolites in rat plasma after intragastric administration of Fu‐Ke‐Zai‐Zao pills were also detected by the same analytical method. A total of 36 compounds were identified, including 21 prototypes and 15 metabolites. The latter were generated through the metabolic pathways of methylation and glucuronidation, and glucuronidated metabolites were the main constituents in the plasma. This is the first systematic study on the chemical constituents and metabolic profiling of Fu‐Ke‐Zai‐Zao pills, and the results provide valuable chemical information for further elucidating pharmacological effects and mechanism of action of Fu‐Ke‐Zai‐Zao pills. This article is protected by copyright. All rights reserved
Article
Two novel phenanthrenoids, juncuenin H (1) and dijuncuenin B (2), together with eight known phenanthrenoids, effusol (3), dehydroeffusol (4), juncusol (5), dehydrojuncusol (6), juncuenin B (7), dehydrojuncuenin B (8), juncuenin A (9), and dehydrojuncuenin A (10), were isolated from the underground parts of Juncus setchuenensis. The structures of the compounds were determined by 1D and 2D NMR and mass spectroscopy. The anxiolytic activities of compounds 1, 6, 9, and 10 were evaluated. In order to explore the mechanisms underlying their anxiolytic activities, the levels of serotonin (5-HT), dopamine (DA), and their metabolites in the cerebral cortex and hippocampus of mice treated with compound 1 were determined by quantitative mass spectrometry. The mice treated with compound 1 had significantly lower levels of 5-HT, 3-methoxytyramine (3-MT), 5-hydroxyindole-3-acetic acid (5-HIAA), homovanillic acid (HVA), and 3, 4-dihydroxyphenylacetic acid (DOPAC) in the cerebral cortex than those of the vehicle control-treated mice. The levels of HVA and 5-HIAA in the hippocampus were also significantly lower in the mice treated with compound 1 than in the control group mice. These results suggest that the metabolic changes, reflected in the levels of DA and/or 5-HT, may contribute to the anxiolytic activity of the phenanthrenoids studied herein.
Thesis
L’hépatite C est une maladie affectant aujourd’hui 170 millions d’individus dans le monde. Cette maladie est causée par le virus de l'hépatite C (VHC). Les nouveaux traitements récemment mis sur le marché, visant à soigner l’hépatite C, sont très onéreux et donc inaccessibles pour les pays du Sud. De plus, l’utilisation de ces nouvelles molécules engendre l’apparition de mutation de résistance virale responsable de l’échec des traitements pour 5 à 10% des patients. La découverte de nouveaux antiviraux est donc toujours indispensable. Les plantes utilisées en médecine traditionnelle depuis des siècles sont une source de composés bio-actifs très intéressante. L’utilisation de ces plantes ou de composés naturels en complément des molécules utilisées en thérapie classique, permettrait de réduire significativement le coût de ces traitements et de les rendre accessibles à davantage de patients.L’epigallocatéchine-3-gallate (EGCG) et la delphinidine sont des molécules naturelles issues respectivement du thé vert et des fruits rouges. Ces deux molécules inhibent l’étape d’entrée du VHC dans les cellules hépatocytaires. Nous avons montré que l'EGCG et la delphinidine inhibent cette étape virale dans les hépatocytes en déformant les particules et bloquant ainsi leur attachement à la surface cellulaire. Nous nous sommes ensuite intéressés au processus engendrant cette déformation qui est probablement lié à l’agrégation des glycoprotéines d’enveloppe virale.Nous avons procédé au criblage d’extraits bruts de plantes extrêmophiles tunisiennes et mis en évidence que l’extrait brut de rhizome de Juncus maritimus inhibait l’étape de réplication du VHC. Le J. maritimus est une plante fortement présente dans les sols arides en Tunisie mais également sur les côtes françaises. En collaboration avec le laboratoire de Pharmacognosie de Lille et grâce à un fractionnement bioguidé, le principe actif a pu être isolé. Il s’agit du déhydrojuncusol qui inhibe la réplication virale avec une concentration effective médiane de 1,31 µM. De plus, nous avons montré que le déhydrojuncusol pouvait inhiber la réplication de virus présentant des mutations de résistance aux traitements actuels ciblant la protéine virale NS5A. Nous avons cherché à identifier la cible virale du déhydrojuncusol et il semblerait que ce soit également la protéine NS5A.Les résultats obtenus dans cette thèse confortent l’hypothèse que des molécules naturelles pourraient être utilisées dans le traitement de l’hépatite C.
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Neuroblastoma (NB) is the most predominant extracranial solid tumor of infancy in the world. However, current chemotherapy has limited efficacy for more advanced stages of NB due to acquired chemoresistance or acute toxicity in NB patients. Therefore, effective novel anti-NB drugs are desperately needed. The present study aimed to investigate the effects of dehydroeffusol (DHE), a phenanthrene isolated from J. effuses, on NB cells and its underlying mechanism. The results showed that DHE treatment effectively inhibited NB cell viability in a dose-dependent manner. Moreover, DHE treatment suppressed the epithelial-mesenchymal transition (EMT) process in NB cells by promoting the expression of E-cadherin (E-cad) and restraining the expressions of N-cadherin (N-cad) and vimentin. Also, the invasive capacity and expression of MMP-2 and MMP-9 in NB cells were inhibited by DHE. Furthermore, DHE suppressed the hedgehog (Hh) and the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in NB cells. In conclusion, DHE effectively inhibited the viability and EMT through inactivating the Hh and the Akt/mTOR signaling pathways in NB cells, providing a novel evidence that DHE may be a potential anti-NB drug candidate.
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Although phenanthrenes are considered to constitute a relatively small group of natural products, discovering new phenanthrene derivatives and evaluating their prospective biological activities have become of great interest to many research groups worldwide. Based on 160 references, this review covers the phytochemistry and pharmacology of 213 naturally occurring phenanthrenes that have been isolated between 2008 and 2016. More than 40% of the 450 currently known naturally occurring phenanthrenes were identified during this period. The family Orchidaceae is the most abundant source of these compounds, although several new plant families and genera have been involved in the search for phenanthrenes. The presence of certain substituent patterns may be restricted to specific families; vinyl-substituted phenanthrenes were reported only from Juncaceae plants, and prenylated derivatives occur mainly in Euphorbiaceae species. Therefore, these compounds also can serve as chemotaxonomic markers. Almost all of the newly isolated compounds have been studied for their biological activities (e.g., potential cytotoxic, antimicrobial, anti-inflammatory, and antioxidant effects), and many of them showed multiple activities. According to the accumulated data, denbinobin, with a novel mechanism of action, has great potential as a lead compound for the development of a new anticancer agent.
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A new sesquilignan effususin E (1) and a new long chain fatty enamide effususin F (2), together with eight known compounds were isolated from the medullae of Juncus effusus. The structures of 1 and 2 were elucidated by detailed spectroscopic analysis including H-1 and C-13 NMR, COSY, HSQC, HMBC, and HRMS, while the structures of the known compounds were deduced from comparison of their spectral data with those in the literature. The new compounds 1 and 2 were evaluated against five human cancer cell lines (SHSY-5Y, SMMC-7721, HepG-2, Hela, and MCF-7) by CCK-8 assay, but only 1 exhibited weak cytotoxic activity against SMMC-7721 with IC50 value of 57.5 mu m. Inhibitory effects of 1 and 2 on nitric oxide (NO) production in lipopolysaccharide-induced RAW264.7 macrophages were also evaluated, and they were found to exhibit good inhibitory activities with IC50 values of 8.59 and 13.73 mu m, respectively.
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The present study has focused on an investigation of the antibacterial effects of Juncus inflexus and the isolation and identification of its active compounds. Eleven phenanthrenes were isolated from a methanolic extract of the roots. Four compounds (jinflexins A-D, 1-4) are new natural products, while seven phenanthrenes [juncuenins A (5), B (6), and D (8), juncusol (7), dehydrojuncuenins A (9) and B (11), and dehydrojuncusol (10)] were isolated for the first time from the plant. Jinflexin D (4) is a dimer with an unprecedented heptacyclic ring system. The absolute configurations of the new compounds were determined by TDDFT-ECD calculations, and their enantiomeric purity was checked by chiral HPLC analysis. Extracts of different polarity (n-hexane, dichloromethane, and ethyl acetate) were evaluated for their antimicrobial effects against methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase (ESBL)-producing Citrobacter freundii, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, multiresistant Acinetobacter baumannii, and Pseudomonas aeruginosa. The MIC values of the isolated compounds were determined by a microdilution method. Jinflexin B (2), juncusol (7), juncuenin D (8), and dehydrojuncuenin B (11) showed significant activity (MIC value range 12.5-100 μg/mL) against MRSA strains.
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A palladium-catalyzed domino intermolecular C(sp2)-H activation reaction of two aryl iodides is reported. This simple palladium catalytic system shows good activity.
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Objective: To rapidly recognize and identify phenanthrenes in Juncus effusus and J. setchuensis. Methods: HPLC-ESI-MS method was used to investigate the ESI-MS characteristics of those phenanthrenes, to screen, and to identify phenanthrenes in J. effusus and J. setchuensis. Results: Under negative mode, phenanthrenes were inclined to loss two hydrogens, which presumably caused by the cyclization of vinyl and aromatic ring; Furthermore, the loss of C=O could be also observed. Fragmentation pathway of phenanthrenes in ESI as a negative ion mode was summarized. Twenty-one phenanthrenes were rapidly detected from the extracts of J. effusus and J. setchuensis. Among them, six compounds were accurately identified by comparison with reference substances; The structures of five compounds were inferred according to their MS spectrum and polarity. Conclusion: HPLC-ESI-MS provides not only a new technique for the rapid identification of phenanthrenes from complex matrix, but also an effective method for the target separation of constituents in Chinese materia medica.
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Context: Anxiety is a common psychological disorder, often occurring in combination with depression, but therapeutic drugs with high efficacy and safety are lacking. Orcinol glucoside (OG) was recently found to have an antidepressive action. Objective: To study the therapeutic potential of OG and orcinol monohydrate (OM) as anxiolytic agents. Materials and methods: Anxiolytic effects in mice were measured using the elevated plus-maze, hole-board, and open-field tests. Eight groups of mice were included in each test. Thirty minutes before each test, mice in each group received one oral administration of OG (5, 10, or 20 mg/kg), OM (2.5, 5, or 10 mg/kg), the positive control diazepam (1 or 5 mg/kg), or control vehicle. Each mouse underwent only one test. Uptake of orcinol (5 mg/kg) in the brain was qualitatively detected using the HPLC-MS method. Results: OG (5, 10, and 20 mg/kg) and OM (2.5 and 5 mg/kg) increased the time spent in open arms and the number of entries into open arms in the elevated plus-maze test. OG (5 and 10 mg/kg) and OM (2.5 and 5 mg/kg) increased the number of head-dips in the hole-board test. At all tested doses, OG and OM did not significantly affect the locomotion of mice in the open-field test. Orcinol could be detected in the mouse brain homogenates 30 min after oral OM administration, having confirmed that OM is centrally active. Discussion and conclusion: The results demonstrated that OG and OM are anxiolytic agents without sedative effects, indicating their therapeutic potential for anxiety.
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Six phenanthrenes, 2-methoxy-7-hydroxy-1-methyl-5-vinyl phenanthrene (1), juncusin (2), dehydroeffusol (3), juncusol (4), effusol (5), and dehydroeffusal (6), were isolated from the medullae of Juncus effusus L. Compounds 1 and 2 were identified as being new structures, and both of them showed anxiolytic activity at dosages of 10 and 2.5 mg/kg, respectively.
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Dehydroeffusol is a naturally occurring phenanthrene isolated from Juncus effusus. In the context of screening new drugs against gastrointestinal spasms, we investigated its effects on isolated rat jejunum in vitro. Dehydroeffusol (30-90 µM) slightly and transiently enhanced contractions in a concentration-dependent manner but significantly inhibited the contractions induced by KCl (100 mM), (±)-Bay-K8644 (5 µM), pilocarpine (90 µM), and histamine (100 µM). These results show that dehydroeffusol may antagonize the spasmogenic activity of various agents, and therefore, could be a promising agent in the treatment of spasms. Its potential spasmolytic mechanism is also discussed.
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This review examines the state of the field for chemically mediated interactions involving marine angiosperms (seagrasses, mangroves, and salt marsh angiosperms). Small-scale interactions among these plants and their herbivores, pathogens, fouling organisms, and competitors are explored, as are community-level effects of plant secondary metabolites. At larger spatial scales, secondary metabolites from marine angiosperms function as reliable cues for larval settlement, molting, or habitat selection by fish and invertebrates, and can influence community structure and ecosystem function. Several recent studies illustrate the importance of chemical defenses from these plants that deter feeding by herbivores and infection by pathogens, but the extent to which allelopathic compounds kill or inhibit the growth of competitors is less clear. While some phenolic compounds such as ferulic acid and caffeic acid act as critical defenses against herbivores and pathogens, we find that a high total concentration of phenolic compounds within bulk plant tissues is not a strong predictor of defense. Residual chemical defenses prevent shredding or degradation of plant detritus by detritivores and microbes, delaying the time before plant matter can enter the microbial loop. Mangroves, marsh plants, and seagrasses remain plentiful sources of new natural products, but ecological functions are known for only a small proportion of these compounds. As new analytical techniques are incorporated into ecological studies, opportunities are emerging for chemical ecologists to test how subtle environmental cues affect the production and release of marine angiosperm chemical defenses or signaling molecules. Throughout this review, we point to areas for future study, highlighting opportunities for new directions in chemical ecology that will advance our understanding of ecological interactions in these valuable ecosystems.
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Our continuing survey of phototoxins from higher plants has led to the isolation and identification from the common rush, Juncus effusus L., of the phenanthrene, dehydroeffusol (1), and the dihydrophenanthrene, juncusol (2), compounds that display enhanced antimicrobial activities in light. The antimicrobial activities (minimum inhibitory concentrations) for these compounds against methicillin-resistant and -sensitive Staphylococcus aureus and Candida albicans were increased 16- and two-fold, respectively, by irradiation with ultraviolet A (UVA). Photosensitized DNA-binding activities (as possible covalent bond formation) of these compounds were determined by using restriction enzymes and a specially prepared 1.5 kb DNA fragment. Under UVA irradiation, dehydroeffusol strongly inhibited all the restriction enzymes (KpnI, XbaI, PmeI, DraI, PacI and BciVI) that have at least one 5'-TpA sequence in their recognition sites. Weak inhibitions were found for the restriction enzymes EcoRI, SacI, BamHI, SalI, PstI and HindIII, which do not possess a 5'-TpA sequence at their restriction sites and the restriction site sequences of which consist of all bases, A, T, G and C. Trace or no inhibition was found for AscI and SmaI, the restriction site sequences of which are composed of only C and G. The results indicate the necessity of thymine (adenine) for the photosensitized DNA-binding activity of dehydroeffusol. A strong inhibition against SphI, which does not have a 5'-TpA sequence in the restriction sequence, indicates that there are possibly other binding sequence(s) for dehydroeffusol. With juncusol and UVA, strong inhibitions for KpnI and BciVI and trace inhibitions for PacI, XbaI, PmeI and DraI were found. This result also showed a preference of juncusol for 5'-TpA, but the preference could be more selective than that of dehydroeffusol depending on the surrounding sequences of 5'-TpA in the respective restriction sites. A strong inhibition of SphI by juncusol with UVA also indicated the existence of an unknown binding sequence for this compound. Generally, the DNA-binding activity of this compound was weaker than that of dehydroeffusol.
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Six novel 9,10-dihydrophenanthrene metabolites have been isolated from the aquatic plant Juncus effusus, together with the already known juncusol, juncunol and effusol. The structures of the compounds have been defined on spectroscopic grounds. Two of them showed a good antitumour activity.
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Nine 9,10-dihydrophenanthrenes, seven of them described for the first time, have been isolated in a further investigation of Juncus effusus. The structures have been defined on the basis of the spectral properties of the compounds. All the dehydrophenanthrene metabolites present in the plant have been tested for their cytotoxic properties and many of them have been found to have a good in vitro activity.
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The medullae of Juncus effusus yielded two new phenanthrene derivatives, dehydroeffusol and dehydroeffusal. Their structures were determined by spectral data.
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Eight aromatic monoglycerides and four aromatic diglycerides have been isolated from J. effusus and their structures have been defined by spectroscopic means. Some of the compounds have reasonable antialgal activity on Selenastrum capricornutum.
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Despite or possibly by virtue of the fact that it is one of the most commonly used animal models of anxiety the Elevated Plus-Maze (EPM) results in a wide range of, often contradictory, results following pharmacological experiments. The responses from a questionnaire distributed to 65 groups that have published studies using the EPM in the past 3 years has, along with reference to published reports, enabled some conclusions regarding the influencing factors to be drawn. Some evidence for differential sensitivities between strains exists, with albino rats being more sensitive to the anxiolytic effects of 5-HT3 receptor antagonists and 5-HT1A receptor agonists than pigmented animals. Most important, however, is the manipulation of the animals prior to testing and the aversiveness of the test conditions themselves. Stressing animals before testing (e.g., by moving from holding to test room) or using more aversive test conditions (e.g., elevated light levels) increases sensitivity to potential anxiolytics. Animals that are habituated to gentle handling or tested in less aversive conditions (e.g., EPM with ledges) show reduced likelihood of anxiolytic responses with administration of 5-HT3 antagonists, 5-HT1A agonists, and benzodiazepines.
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The open field test (OFT) is a widely used procedure for examining the behavioral effects of drugs and anxiety. Detailed ethological assessments of animal behavior are lacking. Here we present a detailed ethological assessment of the effects of acute treatment with the benzodiazepines, diazepam (DZ, 1.5mg/kg) and chlordiazepoxide (CDP, 5.0 and 10.0mg/kg), as well as exposure to a non-pharmacological agent, a specific pulsed extremely low frequency magnetic field (MAG) on open field behavior. We examined the duration, frequency and time course of various behaviors (i.e. exploration, walk, rear, stretch attend, return, groom, sit, spin turn, jump and sleep) exhibited by male mice in different regions of a novel open field. Both DZ and CDP consistently reduced the typical anxiety-like behaviors of stretch attend and wall-following (thigmotaxis), along with that of an additional new measure: 'returns', without producing any overall effects on total locomotion. The drugs also differed in their effects. CDP elicited a shift in the locomotor pattern from a 'high explore' to a 'high walk', while DZ mainly elicited alterations in sit and groom. The MAG treatment was repeated twice with both exposures reducing horizontal and vertical (rearing) activity and increasing grooming and spin turns. However, the anxiety-like behaviors of stretch attend and return were marginally reduced by only the first exposure. We conclude that a detailed ethological analysis of the OFT allows not only the detection of specific effects of drugs and non-pharmacological agents (i.e. pulsed magnetic field) on anxiety-like behaviors, but also permits the examination of non-specific effects, in particular those on general activity.